工程化脂质纳米颗粒实现人源化小鼠体内造血干细胞的持久编辑
Engineered lipid nanoparticles for in vivo and durable editing of haematopoietic stem cells within humanized mice
在活体内直接改造造血干祖细胞有望改变多种疾病的治疗格局，但难点在于如何高效靶向静止的人造血干细胞并保持其长期功能。研究筛选了15种脂质纳米颗粒，找到一种与抗CD34抗体偶联后可高效递送信使RNA的颗粒。用基因编辑工具装载后，它能在体外高效编辑人造血干祖细胞；在小鼠股骨内注射后，可编辑红细胞特异性BCL11A增强子，使红细胞长期重新表达胎儿血红蛋白。在携带ELANE突变的人源化中性粒细胞减少模型中，该递送系统也能实现有效编辑并部分恢复中性粒细胞发育。结果显示这种靶向递送不会扰乱造血，具备临床转化潜力。
为什么推荐给您：体内靶向递送实现造血干细胞持久编辑，属新平台技术的重要进展。
不需要生物学背景，多打比方
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摘要Abstract
In vivo genetic engineering of haematopoietic stem and progenitor cells (HSPCs) holds the potential to revolutionize the treatment landscape for numerous diseases. However, despite its transformative potential, it remains hindered by the difficulty in efficiently and specifically targeting quiescent human HSCs while maintaining their long-term functionality. Here, after screening 15 lipid nanoparticles (LNPs), we report an LNP that efficiently delivers reporter mRNA to human HSPCs both in ex vivo and in vivo settings when conjugated with the anti-CD34 antibody (CD34/LNPDP). Using CRISPR/Cas editing cargos, CD34/LNPDP achieves high editing efficiency in human HSPCs ex vivo. Intrafemoral administration of CD34/LNPDP in humanized mice results in efficient editing of the erythroid-specific BCL11A enhancer within human HSPCs, enabling the sustained long-term reactivation of fetal haemoglobin (HbF) expression in erythroid cells. In a humanized neutropaenia model harbouring an ELANE mutation, intrafemoral administration of CD34/LNPDP achieves robust editing, targeting exon 2 of ELANE in human HSPCs, partially restoring neutrophil development impairment under long-term observation. Collectively, CD34-targeted delivery enables in vivo HSPC modification without perturbing haematopoiesis, underscoring its suitability for clinical translation.